Pharmacokinetic study of darbepoetin alfa: Absorption, distribution, and excretion after a single intravenous and subcutaneous administration to rats

Abstract

KRN321 is a hyperglycosylated analogue of recombinant human erythropoietin (rHuEPO, epoetin alfa), and its absorption, distribution, and excretion have been studied after a single intravenous and subcutaneous administration of ¹²⁵I-KRN321 at a dose of 0.5 µg kg⁻¹ to male rats. The half-lives of immunoreactive radioactivity in the terminal phase after intravenous and subcutaneous administration were 14.05 and 14.36 h, respectively, and the bioavailability rate after subcutaneous administration was 47%. The total radioactivity in tissues was lower than that in the serum in all tissues excluding the thyroid gland and skin at the injection site (subcutaneous administration). The maximum concentrations were observed in the bone marrow or skin at the injection site followed by the thyroid gland, kidneys, adrenal glands, spleen, lungs, stomach and bladder. The radioactivity found in trichloroacetic acid-precipitated fractions suggested that a high-molecular weight compound, unchanged or mixed with endogenous protein, distributed to the tissues after administration. The whole-body autoradiographic findings in both groups were in agreement with the tissue distribution mentioned above. The blood cell uptake of KRN321 was low for both groups. The excretion ratios of radioactivity into urine and faeces up to 168 h were 71.4 and 14.1% after the intravenous administration and 74.9 and 12.0% after the subcutaneous administration. There was no difference in the excretion profile of radioactivity between the two groups.

Key Words::

• KRN321
• darbepoetin alfa
• absorption
• distribution
• excretion

Acknowledgements

The authors wish to thank Dr Takenori Natori and Yoshimi Shindo, Pharmaceutical Development Laboratories, Pharmaceutical Division, Kirin Brewery Co., Ltd, for their continuous and valuable support. We also thank the personnel who were associated with this study at Panapharm Laboratories Co. Ltd regarding the implementation of animal studies.